The overall goal is to understand the genetic basis of, and identify quantitative trait loci for, risk factorsfor cardiovascular disease including LDL density, HDL level, and apoB level, as well as PLTP activity, in families with familial combined hyperlipidemia (FCHL). FCHL is the most common lipid disorder leading to premature vascular disease. Small dense LDL, depressed HDL level, and elevated apoB level are important atherogenic components of the phenotype of FCHL. PLTP activity is an important covariate. Use of four large FCHL families will increase sample homogeneity and joint consideration of covariates, including plasma lipoprotein transfer protein activity, will improve power to detect linkage for these loci. These investigations consider large families with FCHL and evidence of Mendelian segregation of each trait, for whom a 10 cM genomic scan has already been completed, allowing efficient mapping studies of these atherogenic FCHL-related phenotypes. Three loci with significant evidence of linkage were identified for adjusted LDL size (peak particle diameter), using both Iod score and newer Markov chain Monte Carlo (MCMC) methods in analyses of both each family separately and the families combined. Usng these methods for complex traits is expected to result in detection of significant linkage evidence for HDL and apoB level. These will be followed by fine mapping and efforts to identify the underlying genes, beginning with LDL size/density traits. Mapping followed by identification of previously undetected genes for these traits will advance both the basic biology of lipid disorders and the potential to diagnose, prevent, and treat vascular disease.